It has been a goal in the drug delivery field to treat a disease by prolonged delivery of a beneficial agent, such as a drug, at a controlled rate. Various approaches have been taken toward this end. For example, implantable diffusional systems have been used to deliver a drug that is released by simple diffusion. In another approach, osmotic delivery systems have been used to provide more accurately controlled delivery than simple diffusion. The osmotic delivery systems can be implanted into a living organism to release the beneficial agent in a controlled manner over a preselected administration period.
In general, implantable osmotic delivery systems operate by imbibing fluid from the outside environment and releasing a corresponding amount of the beneficial agent. An implantable osmotic delivery system typically contains as part of its wall a semipermeable membrane that allows fluid to pass through from the external environment but not particles. The semipermeable membrane is next to a compartment containing an osmotic agent that is capable of imbibing water. When the system is placed in a fluid environment, water is imbibed from the environment into the system by the osmotic agent, resulting in expansion of the osmotic agent. The expanded osmotic agent generates a pressure on the beneficial agent, which is located directly next to the osmotic agent or on the other side of a movable partition or piston from the osmotic agent, and forces the beneficial agent to pass through an opening to the outside environment. Various osmotic delivery systems have been described in, for example, U.S. Pat. Nos. 6,132,420; 5,985,305; 5,938,654; 5,795,591; 5,728,396; 5,595,759; 5,413,572; 5,368,863; 4,783,337; and 4,609,374, which are incorporated by reference herein in their entirety.
Most current implantable osmotic delivery systems comprise a semipermeable membrane that is in liquid communication with an osmotic agent or engine compartment, a movable partition or piston separating the engine compartment from the beneficial agent compartment or reservoir, and an orifice or exit that is in communication with both the beneficial agent in the reservoir and the exterior of the osmotic delivery system.
Beneficial agent delivery from implantable osmotic delivery systems can be accomplished in a variety of ways. The beneficial agent can be delivered in a controlled manner that is dependent upon the push power profile of the osmotic engine. The beneficial agent delivery rate can also be varied. For example, the flow of beneficial agent from the system can be partially retarded by placing an elastic membrane or band over the exit (for example, U.S. Pat. No. 5,209,746, which is incorporated by reference herein in its entirety). The elastic membrane or band stretches with an increase of pressure in the system until the internal pressure causes the membrane to separate sufficiently from the orifice to permit escape of the beneficial agent (this type of delivery can be termed pulsatile delivery).
Most current implantable osmotic delivery systems contain engines that comprise dry tablets comprising the osmotic agent. Due to machining and tableting tolerances, the osmotic tablet is generally slightly smaller than the compartment in which the tablet is placed. A filler can be used to fill the gap between the tablet and the compartment wall (for example, U.S. Pat. No. 6,132,420 which is incorporated by reference herein in its entirety). However, there are potential disadvantages to this kind of engine.
For instance, an osmotic delivery system that includes an osmotic engine comprising a tableted osmotic composition may require a startup time that is undesirably long. As it is used herein, the term “startup time” refers to the time from introduction of the osmotic system into the environment of use until the active agent is actually delivered from the osmotic system at a rate not less than approximately 70% of the intended steady-state rate (See, for example, U.S. Pat. No. 5,985,305, which is incorporated by reference herein in its entirety). The time required for the intended steady-state delivery rate is dependent upon a number of factors. For instance, the semipermeable membrane must be wet and fluid must flow through the semipermeable membrane into the osmotic engine compartment. After passing through the semipermeable membrane, fluid must also wet the osmotic tablets sufficiently to cause them to swell. The swelling of the osmotic tablet material then moves the movable partition or piston between the osmotic tablet and the beneficial agent toward the exit or orifice. This movement of the movable partition or piston toward the exit or orifice pushes the beneficial agent to and through the exit or orifice. Due to the manner in which tableted osmotic engines are manufactured, the time required to achieve movement of the movable partition or piston such that startup is achieved may constitute a significant portion of the anticipated life of the osmotic delivery system.
In particular, during the manufacture of tableted osmotic engines or during the loading of osmotic engine tablets into the engine compartment of an osmotic delivery system, air is typically entrapped within the tableted composition, between the filler and the engine tablet, between the filler and a wall of the osmotic delivery system, or inside the filler itself, particularly where a dry filler material is used. The compressibility of the tableted composition results in a delay in startup as the entrapped air is compressed and causes the osmotic engine to expand at a rate that is less than proportional to the volume of water imbibed through the semipermeable membrane, at least until startup is achieved. If too much air is entrapped during the manufacture of the tableted osmotic engine or during assembly of the osmotic delivery system, the startup time of the system may be undesirably high for a desired application. Moreover, the amount of air entrapped may vary from one system to another, resulting in startup performance that varies significantly from system to system.
Another potential disadvantage of an osmotic delivery device that includes an osmotic engine formed using a tableted osmotic composition is that such an osmotic engine requires at least one manufacturing step that may be avoided. In a presently available system (DUROS® system, ALZA Corporation, Mountain View, Calif.), the osmotic engine contains both the tableted osmotic composition and a filler composition, which serves to reduce or minimize entrapped air within the engine compartment. To manufacture such an engine, the engine filler (or compound used to fill in gaps around the tablets) is loaded into the engine compartment first. After the filler is loaded, one or more osmotic tablets are positioned within the same compartment such that the filler flows around the tablets. In some instances, excess filler may overflow the engine compartment. Where such is the case, it may not be certain how much filler is left in each engine and the ratio of osmotic agent to filler may vary among engines. However, if the osmotic material included in the engine itself worked to minimize or reduce entrapped compressible gas within the compartment, the step of loading the filler into the engine compartment and the uncertainties that such a step may introduce could be eliminated. Therefore, it would be an improvement in the art to provide an osmotic delivery system that includes an osmotic engine that is easily manufactured, works to reduce or minimize entrapped air, and possesses a more predictable composition from system to system.